Nerve growth factor (NGF) is a naturally occurring secreted protein which consists of an alpha, beta and gamma polypeptide chain. NGF is a member of the neurotrophin family and is implicated in a number of different roles. NGF promotes survival and differentiation of sensory and sympathetic neurons and signals via two membrane bound receptors, p75, a low affinity NGF receptor and TrkA, a transmembrane tyrosine kinase and a high affinity NGF receptor. The binding of NGF to TrkA or p75 results in an upregulation of neuropeptides in sensory neurons.
The use of NGF antagonists to treat pain and pain sensitivity in humans has been described (Cattaneo A., Curr. Op. Mol. Ther. 2010 12(1):94-106). For example, International Patent Application No. WO 2006/131951 describes a humanised form of the rat alphaD11 (αD11) monoclonal antibody. The αD11 antibody has binding specificity to mouse NGF, but is also known to bind to human and rat forms of NGF. Humanisation of the αD11 rat derived monoclonal antibody is required prior to administration to humans in order to minimise the production of neutralising antibodies which result from a human anti-mouse antibody (HAMA) response being mounted against rodent derived antibodies. Furthermore, the replacement of mouse constant domains with human constant domains allows downstream effector functions to be selected for.
Pain management in felines is currently provided through administration of analgesic drugs of several classes, including local and general anaesthetics, opioid analgesics, α2 agonists, non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Each of these needs to be administered frequently and also has limitations in efficacy and safety. There is accordingly a need for an infrequently dosed, long lasting and efficacious form of pain relief for felines suffering from chronic pain, such as those with neuropathic or oncologic pain.
While NGF is expressed in feline tissues, only a partial clone is available of its sequence. This partial mRNA sequence is defined in Genbank Accession number EF065101 (See ncbi.nlm.nih.gov. Felis catus nerve growth factor beta-like mRNA). No antagonist to feline NGF has been described, nor has the use of blocking NGF mediated signalling in felines to prevent or alleviate pain. The use in felines of known antibodies which act as anti-NGF antagonists in other species would not be feasible as it cannot be determined with certainty whether an antibody with binding specificity to nerve growth factor expressed in another species would also bind to feline nerve growth factor. Furthermore, there also exists the possibility that neutralising antibodies may be produced against any such administered antibody, as it would be recognised as foreign by the feline immune system. Any production of neutralising antibodies would limit the long term administration of the antibody to felines, this being a particularly important requirement when treating a chronic pain related condition or a cancerous condition. Further still, the administration to a feline of an anti-NGF antibody derived from another species may exhibit cross-reactivity to other target epitopes which may be present in felines, but not present in the species from which the antibody was originally derived. Accordingly, there is a serious need for binding members which act as antagonists of feline NGF and which retain high levels of binding affinity and avidity, while avoiding the production of neutralising antibodies there against, for use in pain management in felines.